1. Field of the Invention
The present invention relates to novel compounds that function as enzyme inhibitors, and particularly to a new class of non-peptidic inhibitors of proteolytic enzymes.
2. Background Art
Proteases are enzymes that cleave proteins at single, specific peptide bonds. Proteases can be classified into four generic classes: serine, thiol or cysteinyl, acid or aspartyl, and metalloproteases (Cuypers et al., J. Biol. Chem. 257:7086 (1982)). Proteases are essential to a variety of biological activities, such as digestion, formation and dissolution of blood clots, reproduction and the immune reaction to foreign cells and organisms. Aberrant proteolysis is associated with a number of disease states in man and other mammals. The human neutrophil proteases, elastase and cathepsin G, have been implicated as contributing to disease states marked by tissue destruction. These disease states include emphysema, rheumatoid arthritis, corneal ulcers and glomerular nephritis. (Barret, in Enzyme Inhibitors as Drugs, Sandler, ed., University Park Press, Baltimore, (1980)). Additional proteases such as plasmin, C-1 esterase, C-3 convertase, urokinase, plasminogen activator, acrosin, and kallikreins play key roles in normal biological functions of mammals. In many instances, it is beneficial to disrupt the function of one or more proteolytic enzymes in the course of therapeutically treating a mammal.
Serine proteases include such enzymes as elastase (human leukocyte), cathepsin G, plasmin, C-1 esterase, C-3 convertase, urokinase, plasminogen activator, acrosin, chymotrypsin, trypsin, thrombin, factor Xa and kallikreins.
Human leukocyte elastase is released by polymorphonuclear leukocytes at sites of inflammation and thus is a contributing cause for a number of disease states. Cathepsin G is another human neutrophil serine protease. Compounds with the ability to inhibit the activity of these enzymes are expected to have an anti-inflammatory effect useful in the treatment of gout, rheumatoid arthritis and other inflammatory diseases, and in the treatment of emphysema. Chymotrypsin and trypsin are digestive enzymes. Inhibitors of these enzymes are useful in treating pancreatitis. Inhibitors of urokinase and plasminogen activator are useful in treating excessive cell growth disease states, such as benign prostatic hypertrophy, prostatic carcinoma and psoriasis.
The serine protease thrombin occupies a central role in hemostasis and thrombosis, and as a multifactorial protein, induces a number of effects on platelets, endothelial cells, smooth muscle cells, leukocytes, the heart, and neurons (Tapparelli et al., Trends in Pharmacological Sciences 14:366-376 (1993); Lefkovits and Topol, Circulation 90(3): 1522-1536(1994); Harker, Blood Coagulation and Fibrinolysis 5 (Suppl 1):S47-S58 (1994)). Activation of the coagulation cascade through either the intrinsic pathway (contact activation) or the extrinsic pathway (activation by exposure of plasma to a non-endothelial surface, damage to vessel walls or tissue factor release) leads to a series of biochemical events that converge on thrombin. Thrombin cleaves fibrinogen ultimately leading to a hemostatic plug (clot formation), potently activates platelets through a unique proteolytic cleavage of the cell surface thrombin receptor (Coughlin, Seminars in Hematology 31(4):270-277 (1994)), and autoamplifies its own production through a feedback mechanism. Thus, inhibitors of thrombin function have therapeutic potential in a host of cardiovascular and non-cardiovascular diseases, including: myocardial infarction; unstable angina; stroke; restenosis; deep vein thrombosis; disseminated intravascular coagulation caused by trauma, sepsis or tumor metastasis; hemodialysis; cardiopulmonary bypass surgery; adult respiratory distress syndrome; endotoxic shock; rheumatoid arthritis; ulcerative colitis; induration; metastasis; hypercoagulability during chemotherapy; Alzheimer""s disease; Down""s syndrome; fibrin formation in the eye; and wound healing. Other uses include the use of said thrombin inhibitors as anticoagulants either embedded in or physically linked to materials used in the manufacture of devices used in blood collection, blood circulation, and blood storage, such as catheters, blood dialysis machines, blood collection syringes and tubes, blood lines and stents.
Factor Xa is another serine protease in the coagulation pathway. Factor Xa associates with factor Va and calcium on a phospholipid membrane thereby forming aprothrombinase complex. This prothrombinase complex then converts prothrombin to thrombin (Claeson, Blood Coagulation and Fibrinolysis 5:411-436 (1994); Harker, Blood Coagulation and Fibrinolysis 5 (Suppl 1):S47-S58 (1994)). Inhibitors of factor Xa are thought to offer an advantage over agents that directly inhibit thrombin since direct thrombin inhibitors still permit significant new thrombin generation (Lefkovits and Topol, Circulation 90(3):1522-1536 (1994); Harker, Blood Coagulation and Fibrinolysis 5 (Suppl 1):S47-S58 (1994)).
A need continues to exist for non-peptidic compounds that are potent and selective protease inhibitors, and which possess greater bioavailability and fewer side-effects than currently available protease inhibitors. Accordingly, new classes of potent protease inhibitors, characterized by potent inhibitory capacity and low mammalian toxicity, are potentially valuable therapeutic agents for a variety of conditions, including treatment of a number of mammalian proteolytic disease states.
The present invention is directed to novel cyclic oxyguanidine compounds having Formulae I and II (below). Also provided are processes for preparing compounds of Formulae I and II, and pharmaceutical compositions comprising a compound of Formula I or II and one or more pharmaceutically acceptable carriers or diluents. The novel compounds of the present invention are potent inhibitors of proteases, especially trypsin-like serine proteases, such as chymotrypsin, trypsin, thrombin, plasmin and factor Xa. Certain of the compounds exhibit antithrombotic activity via direct, selective inhibition of thrombin, or are intermediates useful for forming compounds having antithrombotic activity.
The invention includes a composition for inhibiting loss of blood platelets, inhibiting formation of blood platelet aggregates, inhibiting formation of fibrin, inhibiting thrombus formation, and inhibiting embolus formation in a mammal, comprising a compound of the invention in a pharmaceutically acceptable carrier. These compositions may optionally include anticoagulants, antiplatelet agents, and thrombolytic agents. The compositions can be added to blood, blood products, or mammalian organs in order to effect the desired inhibitions.
Also provided are methods of inhibiting or treating aberrant proteolysis in a mammal, and methods for treating myocardial infarction; unstable angina; stroke; restenosis; deep vein thrombosis; disseminated intravascular coagulation caused by trauma, sepsis or tumor metastasis; hemodialysis; cardiopulmonary bypass surgery; adult respiratory distress syndrome; endotoxic shock; rheumatoid arthritis; ulcerative colitis; induration; metastasis; hypercoagulability during chemotherapy; Alzheimer""s disease; Down""s syndrome; fibrin formation in the eye; and wound healing. Other uses of compounds of the invention are as anticoagulants either embedded in or physically linked to materials used in the manufacture of devices used in blood collection, blood circulation, and blood storage, such as catheters, blood dialysis machines, blood collection syringes and tubes, blood lines and stents.
The invention also includes a method for reducing the thrombogenicity of a surface in a mammal by attaching to the surface, either covalently or noncovalently, a compound of the invention.
In another aspect, the present invention includes processes for preparing an oxyguanidine compound of the invention.
Compounds of the present invention include compounds of Formula I: 
or a solvate, hydrate or pharmaceutically acceptable salt thereof; wherein:
A is one of 
Thus, the compounds of Formula I can be represented by Formulae Ia or Ib: 
or a solvate, hydrate or pharmaceutically acceptable salt thereof.
For each of Formulae I, Ia and Ib, the following values apply:
R1 is one of alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl or heteroaryl, any of which may be optionally substituted;
Z is one of xe2x80x94OSO2xe2x80x94, xe2x80x94SO2Oxe2x80x94, xe2x80x94OC(RyRz)xe2x80x94, or xe2x80x94C(RyRz)Oxe2x80x94;
Ry and Rz are each independently one of hydrogen, alkyl, cycloalkyl, aryl, aralkyl, hydroxyalkyl, carboxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl or carboxy;
R3, R4, R5 and R6 are each independently one of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, trifluoromethyl, halogen, hydroxyalkyl, cyano, nitro, carboxamido, xe2x80x94CO2Rx, xe2x80x94CH2ORx or xe2x80x94ORx, or when present on adjacent carbon atoms, R4 and R3 may also be taken together to form one of xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94 or xe2x80x94(CH2)qxe2x80x94, where q is from 2 to 6, and R5 and R6 are defined as above;
Rx, in each instance, is independently one of hydrogen, alkyl or cycloalkyl wherein said alkyl or cycloalkyl groups may optionally have one or more unsaturations;
Y is one of xe2x80x94Oxe2x80x94, xe2x80x94NR10xe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94CHR10xe2x80x94 or a covalent bond; and
R10, in each instance, is independently one of hydrogen, alkyl, aralkyl, aryl, hydroxy(C2-10)alkyl, amino(C2-10)alkyl, monoalkylamino(C2-10)alkyl, dialkylamino(C2-10)alkyl or carboxyalkyl;
Ra, Rb and Rc are independently hydrogen, alkyl, hydroxy, alkoxy, aryloxy, aralkoxy, alkoxycarbonyloxy, cyano or xe2x80x94CO2Rw, where
Rw is alkyl, cycloalkyl, phenyl, benzyl, 
xe2x80x83where Rd and Re are independently hydrogen, C1-6 alkyl, C2-6 alkenyl or phenyl, Rf is hydrogen, C1-6 alkyl, C2-6 alkenyl or phenyl, Rg is hydrogen, C1-6 alkyl, C2-6 alkenyl or phenyl, and Rh is aralkyl or C1-6 alkyl;
n and nxe2x80x2 are each from zero to 4, preferably zero to 2;
m and mxe2x80x2 are each from zero to 4, preferably zero to 2; and
j and jxe2x80x2 are each from zero to 4, preferably zero to 2;
provided that n, nxe2x80x2, m, mxe2x80x2, j and jxe2x80x2 are not all zero.
A preferred group of compounds falling within the scope of the present invention include compounds of Formulae Ia and Ib wherein:
R1 is one of C6-10 aryl, pyridinyl, thiophenyl (i.e., thiophene), quinazolinyl, quinolinyl or tetrahydroquinolinyl, any of which is optionally substituted by one or two of hydroxy, nitro, trifluoromethyl, halogen, C1-6 alkyl, C6-10 aryl, C1-6 alkoxy, C6-10 ar(C1-6)alkoxy, C1-6 aminoalkyl, C1-6 aminoalkoxy, amino, mono(C1-4)alkylamino, di(C1-4)alkylamino, C2-6 alkoxycarbonylamino, C2-6 alkoxycarbonyl, carboxy, C1-6 hydroxyalkyl, C2-6 hydroxyalkoxy, (C1-6)alkoxy(C2-6)alkoxy, mono- and di-C1-4 alkylamino(C2-6)alkoxy, C2-10 mono(carboxyalkyl)amino, di(C2-10 carboxyalkyl)amino, C6-14 ar(C1-6) alkoxycarbonyl, C2-6 alkynylcarbonyl, C1-6 alkylsulfonyl, C2-6 alkenylsulfonyl, C2-6 alkynylsulfonyl, C6-10 arylsulfonyl, C6-10 ar(C1-6) alkylsulfonyl, C1-6 alkylsulfinyl, C1-6 alkylsulfonamido, C6-10 arylsulfonamido, C6-10 ar(C1-6) alkylsulfonamido, amidino, guanidino, C1-6 alkyliminoamino, formyliminoamino, C2-6 carboxyalkoxy, C2-6 carboxyalkyl, carboxyalkylamino, cyano, trifluoromethoxy, perfluoroethoxy and R13R14NSO2xe2x80x94;
R13 and R14 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocycle, heterocycloalkyl, carboxyalkyl, alkoxycarbonylalkyl, cyano(C2-10)alkyl, hydroxy(C2-10)alkyl, alkoxy(C2-10)alkyl, mono- and di-alkylamino(C2-10)alkyl, or R13 and R14 can be taken together with the nitrogen atom to which they are attached to form a three to seven membered ring, optionally containing one or more heteroatoms in addition to said nitrogen, such as oxygen, sulfur, or nitrogen (NR15), said ring being preferably saturated, and said ring having one or two optional substituents selected from the group consisting of hydroxy, acyloxy, alkoxy, aryloxy, amino, mono- and di-alkylamino, acylamino, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocycle, heterocycloalkyl, carboxyalkyl, alkoxycarbonylalkyl, cyano(C2-10)alkyl, hydroxy(C2-10)alkyl, alkoxy(C2-10)alkyl, mono- and di-alkylamino(C2-10)alkyl, carboxy, alkoxycarbonyl, carboxamido, formyl, alkanoyl, aroyl, aralkanoyl, sulfonyl, alkylsulfonyl, alkoxysulfonyl, sulfonamido, phosphonyl, phosphoramido, and phosphinyl, and wherein R15 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocycle, heterocycloalkyl, carboxyalkyl, alkoxycarbonylalkyl, cyano(C2-10)alkyl, hydroxy(C2-10)alkyl, alkoxy(C2-10)alkyl, mono- and di-alkylamino(C2-10)alkyl, carboxy, alkoxycarbonyl, carboxamido, formyl, alkanoyl, aroyl, aralkanoyl, sulfonyl, alkylsulfonyl, alkoxysulfonyl, sulfonamido, phosphonyl, phosphoramido, and phosphinyl; and
Z is one of xe2x80x94SO2Oxe2x80x94, xe2x80x94OSO2xe2x80x94, xe2x80x94C(RyRz)Oxe2x80x94 or xe2x80x94OC(RyRz)xe2x80x94, where Ry and Rz are each hydrogen. Z is most preferably xe2x80x94SO2Oxe2x80x94.
Preferred compounds include compounds of Formulae Ia and Ib wherein:
R1 is one of phenyl, naphthyl, pyridyl, thiophenyl, quinolinyl or isoquinolinyl, optionally substituted by one or two of chloro, methoxy, methyl, trifluoromethyl, methylsulfonyl, cyano, nitro, amino or dimethylamino;
Z is xe2x80x94SO2Oxe2x80x94;
R3 and R4 are hydrogen or C1-4 alkyl, or R3 and R4 may also be taken together to form xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94;
R5 is one of hydrogen, methyl, methoxy or trifluoromethyl;
R6 is hydrogen;
Y is one of O, NR10 or a covalent bond; and
R10, in each instance, is independently hydrogen, C1-4 alkyl, C2-4 hydroxyalkyl, C2-4 carboxyalkyl, C2-4 aminoalkyl, dimethylamino(C2-8)alkyl, methylamino(C2-8)alkyl.
Yet another preferred group of compounds include compounds of Formulae Ia and Ib wherein:
R1 is phenyl, substituted by one of alkylsulfonyl, arylsulfonyl and R13R14NSO2xe2x80x94,
where R13 and R14 are independently selected from the group consisting of hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C6-10 ar(C1-4)alkyl, pyridyl, pyridyl(C1-4)alkyl, carboxy(C1-6)alkyl, C1-4 alkoxycarbonyl(C1-4)alkyl, cyano(C2-6)alkyl, hydroxy(C2-6)alkyl, C1-4 alkoxy(C2-6)alkyl, mono- and di-(C1-4)alkylamino(C2-6)alkyl, or R13 and R14 can be taken together with the nitrogen atom to which they are attached to form a heterocyclic ring selected from the group consisting of N-morpholino, N-piperazinyl (optionally Nxe2x80x2 substituted with C1-6alkyl, C1-6 hydroxyalkyl, C6-10aryl, C6-10 aryl(C1-6)alkyl, C1-6 alkylsulfonyl, C6-10 arylsulfonyl, C1-6 alkylcarbonyl, morpholino or C6-10 arylcarbonyl), N-pyrrolyl, N-piperidinyl, N-pyrrolidinyl, N-dihydropyridyl, and N-indolyl, wherein said heterocyclic ring can be optionally substituted with one or two of hydroxy, C1-8 alkanoyloxy, C1-6 alkoxy, C6-10 aryloxy, amino, mono- and di-C1-6 alkylamino, C1-8 alkanoylamino, C1-4 alkyl, C3-7 cycloalkyl, C6-10 aryl, C6-10 ar(C1-4)alkyl, heterocycle, heterocycloalkyl, carboxy(C1-6)alkyl, C1-4 alkoxycarbonyl(C1-4)alkyl, cyano(C2-6)alkyl, hydroxy(C2-6)alkyl, C1-4 alkoxy(C2-6)alkyl, mono- and di-(C1-4)alkylamino(C2-6)alkyl, carboxy, C1-6 alkoxycarbonyl, carboxamido, formyl, C1-6 alkanoyl, C6-10 aroyl, C6-10 ar(C1-4)alkanoyl, sulfonyl, C1-6 alkylsulfonyl, C1-6 alkoxysulfonyl, sulfonamido, phosphonyl, phosphoramido, or phosphinyl;
Z is one of xe2x80x94SO2Oxe2x80x94, xe2x80x94CH2Oxe2x80x94 or xe2x80x94OCH2xe2x80x94;
R3 and R4 are hydrogen or C1-4alkyl, or R3 and R4 may also be taken together to form xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94;
R5 is one of hydrogen, methyl, methoxy or trifluoromethyl;
R6 is hydrogen;
Y is one of O, NR10 or a covalent bond; and
R10, in each instance, is independently hydrogen, C1-4 alkyl, C2-4 hydroxyalkyl, C2-4 carboxyalkyl, C2-4 aminoalkyl, dimethylamino(C2-8)alkyl, methylamino(C2-8)alkyl.
The moiety xe2x80x94Zxe2x80x94R1 of Formulae Ia and Ib is attached to the benzene ring in a position ortho-, meta- or para- to Y, with the meta-position being preferred.
Preferred compounds of the present invention are those of Formulae Ia and Ib wherein Y is one of divalent oxygen (xe2x80x94Oxe2x80x94), xe2x80x94NR10xe2x80x94 or a covalent bond, most preferably xe2x80x94Oxe2x80x94, and Z is one of xe2x80x94SO2Oxe2x80x94 or xe2x80x94CH2Oxe2x80x94, most preferably xe2x80x94SO2Oxe2x80x94.
Preferred values of optional substituents on R1 include hydroxy, nitro, trifluoromethyl, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 aminoalkyl, C6-10 aryl, C6-10 ar(C1-6)alkoxy, biphenyl(C1-6)alkoxy C1-6 aminoalkoxy, amino, mono(C1-4)alkylamino, di(C1-4)alkylamino, C2-6 alkoxycarbonylamino, C2-6 alkoxycarbonyl, carboxy, C1-6 hydroxyalkyl, C2-10 mono(carboxyalkyl)amino, bis(C2-10 carboxyalkyl)amino, C6-14 ar(C1-6)alkoxycarbonyl, C2-6 alkynylcarbonyl, C1-6 alkylsulfonyl, C6-10 arylsulfonyl, C2-6 alkenylsulfonyl, C2-6 alkynylsulfonyl, C1-6 alkylsulfinyl, C1-6 alkylsulfonamido, amidino, guanidino, C1-6 alkyliminoamino, formyliminoamino, C2-6 carboxyalkoxy, carboxyalkylamino, cyano, trifluoromethoxy, and perfluoroethoxy.
Additional preferred values of optional substituents on R1 include C1-6 alkylsulfonyl, C6-10 arylsulfonyl, C6-10 ar(C1-6) alkylsulfonyl, C6-10 arylsulfonamido, C6-10 ar(C1-6) alkylsulfonamido, N-morpholinosulfonyl, and R13R14NSO2xe2x80x94, where R13 and R14 are independently selected from the group consisting of hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C6-10 ar(C1-4)alkyl, pyridyl, pyridyl(C1-4)alkyl, carboxy(C1-6)alkyl, C1-4 alkoxycarbonyl(C1-4)alkyl, cyano(C2-6)alkyl, hydroxy(C2-6)alkyl, C1-4 alkoxy(C2-6)alkyl, mono- and di-(C1-4)alkylamino(C2-6)alkyl, or R13 and R14 can be taken together with the nitrogen atom to which they are attached to form a heterocyclic ring selected from the group consisting of N-morpholinosulfonyl, N-piperazinylsulfonyl (optionally Nxe2x80x2 substituted with C1-6 alkyl, C1-6 hydroxyalkyl, C6-10 aryl, C6-10 aryl(C1-6)alkyl, C1-6 alkylsulfonyl, C6-10 arylsulfonyl, C1-6 alkylcarbonyl, morpholino or C6-10 arylcarbonyl), N-pyrrolylsulfonyl, N-piperidinylsulfonyl, N-pyrrolidinylsulfonyl, N-dihydropyridylsulfonyl, N-indolylsulfonyl, wherein said heterocyclic ring can be optionally substituted with one or two of hydroxy, C1-8 alkanoyloxy, C1-6 alkoxy, C6-10 aryloxy, amino, mono- and di-C1-6 alkylamino, C1-8 alkanoylamino, C1-4 alkyl, C3-7 cycloalkyl, C6-10 aryl, C6-10 ar(C1-4)alkyl, heterocycle, heterocycloalkyl, carboxy(C1-6)alkyl, C1-4 alkoxycarbonyl(C1-4)alkyl, cyano(C2-6)alkyl, hydroxy(C2-6)alkyl, C1-4 alkoxy(C2-6)alkyl, mono- and di-(C1-4)alkylamino(C2-6)alkyl, carboxy, C1-6 alkoxycarbonyl, carboxamido, formyl, C1-6 alkanoyl, C6-10 aroyl, C6-10 ar(C1-4)alkanoyl, sulfonyl, C1-6 alkylsulfonyl, C1-6 alkoxysulfonyl, sulfonamido, phosphonyl, phosphoramido, or phosphinyl.
An additional preferred group of compounds are those compounds of Formulae Ia and Ib wherein R1 is heteroaryl or substituted heteroaryl. Preferred R1 heteroaryl groups include pyridyl, pyrazolyl, thiophenyl, chromenyl, benzoxazolyl, benzthiadiazolyl, quinazolinyl, quinolinyl, isoquinolinyl and tetrahydroquinolinyl, with thiophenyl, quinazolinyl, quinolinyl and tetrahydroquinolinyl being more preferred and thiophenyl, isoquinolinyl and quinolinyl especially preferred. Preferred compounds when R1 is substituted heteroaryl include those compounds having one of the heteroaryl groups mentioned as preferred that have one or more, preferably one or two, substituents that are listed in the preceding paragraph. Preferred substituents when R1 is substituted heteroaryl include one or more substituents, preferably 1 to 3 substituents, independently selected from halogen, C1-6 alkyl, C1-6 alkoxy, amidino, guanidino, carboxyalkoxy, carboxyalkylamino, amino, mono(C1-6)alkylamino and/or di(C1-6)alkylamino.
Useful values of R1 include phenyl, chlorophenyl, iodophenyl, dichlorophenyl, bromophenyl, trifluoromethylphenyl, methylsulfonylphenyl, di(trifluoromethyl)phenyl, methylphenyl, t-butylphenyl, methoxyphenyl, dimethoxyphenyl, hydroxyphenyl, carboxyphenyl, aminophenyl, methylaminophenyl, n-butylaminophenyl, amidinophenyl, guanidinophenyl, formyliminoaminophenyl, acetimidoylaminophenyl, methoxycarbonylphenyl, ethoxycarbonylphenyl, carboxymethoxyphenyl, naphthyl, hydroxynaphthyl, cyclohexyl, cyclopentyl, 2-propylbutyl, 5-chloro-2-methoxyphenyl, 2-cyanophenyl, 2-(N-hydroxy)aminophenyl, 2-(4-biphenylmethoxy)phenyl, 2-(3-biphenylmethoxy)phenyl, benzyl, 3-(6-(2,3-dihydro-1,1-dioxobenzo[b]thiophene)phenyl, 2-(phenylsulfonyl)phenyl, 2,4-bis(methylsulfonyl)phenyl, and 2-chloro-4-methylsulfonylphenyl. Additional useful values include 8-quinolinyl, 5-methyl-8-quinolinyl, 4-benzo-2,1,3-thiadiazolyl, 5-chloro-2-thiophenyl, 5-chloro-1,3-dimethyl-4-pyrazolyl, pyridyl, isoquinolinyl, and tetrahydroquinolinyl.
Useful values of R1, when R1 is phenyl substituted by R13R14NSO2xe2x80x94 include 2-(N-methylphenethylaminosulfonyl)phenyl, bis(2-methoxyethyl)aminosulfonylphenyl, 2-N-methyl-(3,4-dimethoxyphenyl)ethylaminosulfonylphenyl, N-methyl-N-ethoxycarbonylmethyl)aminosulfonylphenyl, 2-(N-methyl-N-(2-(2-pyridyl)ethyl)aminosulfonyl)phenyl, 2-(N-propyl-N-(2-(2-pyridyl)ethyl)aminosulfonyl)phenyl, 2-(N-ethyl-N-(4-pyridylmethyl)aminosulfonyl)phenyl, 2-(N-methyl-N-(4-methoxyphenyl)-aminosulfonyl)phenyl, 2-(N-methyl-N-(4-methoxycarbonylphenyl)aminosulfonyl)phenyl, 2-(N-(2-cyanoethyl)-N-(3-pyridylmethyl)aminosulfonyl)phenyl, 2-(N,N-bis-(2-cyanoethyl)aminosulfonyl)phenyl, 2-(N-(2-ethoxycarbonylethyl)-N-benzyl-aminosulfonyl)phenyl, 2-(N-methyl-N-(2-(4-pyridyl)ethyl)aminosulfonyl)phenyl, 2-(N-(ethoxycarbonylmethyl)-N-(2-pyridylmethyl)aminosulfonyl) phenyl, 2-(N,N-,bis(ethoxycarbonylmethyl)aminosulfonyl)phenyl, 2-(N,N-bis-(carboxymethyl)aminosulfonyl)phenyl, 2-(N-methyl-N-(4-carboxyphenyl)aminosulfonyl)phenyl, 2-(N-(2-carboxyethyl)-N-benzylaminosulfonyl)phenyl, 2-(N-(2-cyanoethyl)-N-(2-furanylmethyl)aminosulfonyl)phenyl, 2-(N-ethyl-N-(1-benzyl-3-pyrrolidinyl)aminosulfonyl)phenyl, 2-(N-benzyl-N-(2-(N,N-dimethylamino)ethyl)aminosulfonyl)phenyl, 2-(N-methyl-N-(1-methyl-4-piperidinyl)aminosulfonyl)phenyl, 2-(N-methyl-N-(3-pyridylmethyl)aminosulfonyl)phenyl, 2-(N-ethyl-N-(2-(N,N-dimethylamino)ethyl)aminosulfonyl)phenyl, 2-(2-(4-morpholinyl)ethylaminosulfonyl)phenyl, 2-(N-methyl-N-(2-(N,N-dimethylamino)ethyl)amino sulfonyl)phenyl, N-ethyl-3,4-(methylenedioxy)anilinosulfonylphenyl, 2-(N-methyl-N-(3-(N,N-dimethylamino)propyl)aminosulfonyl)phenyl, and 2-(4-pyridylmethyl-aminosulfonyl)phenyl.
Further useful values of R1, when R1 is phenyl substituted by R13R14NSO2xe2x80x94 include 2-morpholinylsulfonylphenyl, 2-(acetylpiperazinylsulfonyl)phenyl, 2-(4-ethyloxycarbonyl)piperidinylsulfonyl, 2-(4-carboxyl)piperidinylsulfonylphenyl, 3-ethoxycarbonyl-1-piperidinosulfonyl)phenyl, 3-carboxypiperidinosulfonyl)phenyl, 2-methoxycarbonyl-1-pyrrolidinosulfonyl)phenyl, 2-carboxy-1-pyrrolidinosulfonyl)phenyl, 2-(4-methylsulfonylpiperazin-1-ylsulfonyl)phenyl, 2-(4-(2-pyrimidinyl)piperazin-1-ylsulfonyl)phenyl, 2-(4-ethylpiperazin-1-ylsulfonyl)phenyl, 2-(4-(piperidin-1-yl)piperidin-1-ylsulfonyl)phenyl, 2-(4-(ethoxycarbonylmethyl)piperazin-1-ylsulfonyl)phenyl, 2-(4-(carboxymethyl)piperazin-1-ylsulfonyl)phenyl, 2-(4-(2-pyridyl)piperazinyl-sulfonyl)phenyl, 2-(4-phenylpiperazinylsulfonyl)phenyl, 2-(4-benzylpiperazinylsulfonyl)phenyl, 2-(4-(2-methoxyphenyl)piperazinylsulfonyl)phenyl, 2-(4-methylpiperazinylsulfonyl)phenyl, 2-(4-(pyrrolidin-1-yl)piperidin-1-ylsulfonyl)phenyl, and 2-(4-ethoxycarbonyl-1-piperazinylsulfonyl)phenyl.
The groups R3, R4, R5 and R6 in Formulae Ia and Ib substitute for any remaining hydrogen atoms on the benzene ring after allowing for attachment of the moiety xe2x80x94Zxe2x80x94R1. Preferred compounds are those where R3, R4, R5 and R6 are independently hydrogen, C1-4 alkyl, C4-7cycloalkyl, C6-14 aryl, especially C6-10 aryl, C6-10 ar(C1-4)alkyl, trifluoromethyl, halogen, hydroxyalkyl, cyano, nitro, carboxamide, carboxy, alkoxycarbonyl, carboxymethyl, alkoxycarbonylmethyl, or cycloalkyloxycarbonyl.
Alternatively, R3 and R4, when attached to adjacent carbon atoms on the benzene ring, are one of xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94 or xe2x80x94(CH2)qxe2x80x94, where q is from 2 to 6, thereby forming a fused ring. Preferred values of R3 together with R4 include xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94 and xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94. When R3 and R4 together form a fused ring, R5 and R6 are preferably hydrogen.
Useful values of R3, R4, R5 and R6 include hydrogen, methyl, ethyl, chloro, bromo, trifluoromethyl, hydroxymethyl, methoxy, ethoxy, carboxamide, nitro, phenyl, cyclopropyl, hydroxy, isopropyl, methoxycarbonyl, ethoxycarbonyl and benzyl. Useful values of R3 and R4 also include R3 and R4 together forming xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94 or xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94 and R5 and R6 being hydrogen.
Another group of preferred compounds of Formulae Ia and Ib are those wherein:
R3, R4, R5 and R6 are independently one of hydrogen, C1-4 alkyl, C3-8 cycloalkyl, phenyl, benzyl, trifluoromethyl, halogen, hydroxy(C1-4)alkyl, cyano, nitro, carboxamido, carboxy, C1-4 alkoxycarbonyl, C1-4 alkoxymethyl or C1-4 alkoxy; or alternatively, R4 and R3, when present on adjacent carbon atoms, may also be taken together to form one of xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94 or xe2x80x94(CH2)qxe2x80x94, where q is from 2 to 6, and R5 and R6 are as defined above;
Y is one of xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NR10xe2x80x94, or a covalent bond; and
R10, in each instance, is independently hydrogen, C1-6 alkyl, benzyl, phenyl, C2-10 hydroxyalkyl, C2-10 aminoalkyl, C1-4 monoalkylamino(C2-8)alkyl, C1-4 dialkylamino(C2-8)alkyl or C2-10 carboxyalkyl.
In this preferred embodiment, R1 can be one of C6-10 aryl, pyridinyl, thiophenyl (i.e., thiophene), quinazolinyl, quinolinyl or tetrahydroquinolinyl, any of which is optionally substituted by one or two of hydroxy, nitro, trifluoromethyl, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 aminoalkyl, C1-6 aminoalkoxy, amino, mono(C1-4)alkylamino, di(C1-4)alkylamino, C2-6 alkoxycarbonylamino, C2-6 alkoxycarbonyl, carboxy, C1-6 hydroxyalkyl, C2-6 hydroxyalkoxy, C2-10 mono(carboxyalkyl)amino, bis(C2-10 carboxyalkyl)amino, C6-14 ar(C1-6) alkoxycarbonyl, C2-6 alkynylcarbonyl, C1-6 alkylsulfonyl, C2-6 alkenylsulfonyl, C2-6 alkynylsulfonyl, C2-6 alkylsulfinyl, C1-6 alkylsulfonamido, amidino, guanidino, C1-6 alkyliminoamino, formyliminoamino, C2-6 carboxyalkoxy, C2-6 carboxyalkyl, carboxyalkylamino, cyano, trifluoromethoxy, and perfluoroethoxy.
Preferred values of R10 in Formulae Ia and Ib include hydrogen, C1-6 alkyl, C6-10 ar(C1-6)alkyl, C6-10 aryl, C2-10 hydroxyalkyl C2-10 aminoalkyl, C2-7 carboxyalkyl, mono(C1-4 alkyl)amino(C1-8)alkyl, and di(C1-4 alkyl)amino (C1-8)alkyl. Suitable values of R10 include methyl, ethyl, propyl, n-butyl, benzyl, phenylethyl, 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, 2-aminoethyl, 2-carboxymethyl, 3-carboxyethyl, 4-carboxypropyl and 2-(dimethylamino)ethyl.
Preferred values of Ra, Rb and Rc in Formulae Ia and Ib are hydrogen, hydroxy, C1-6alkyl, C1-6 alkoxy, cyano or xe2x80x94CO2Rw, where Rw, in each instance, is preferably one of C1-4alkyl, C4-7cycloalkyl or benzyloxycarbonyl. Suitable values of Ra, Rb and Rc include hydrogen, methyl, ethyl, propyl, n-butyl, hydroxy, methoxy, ethoxy, cyano, xe2x80x94CO2CH3, xe2x80x94CO2CH2CH3 and xe2x80x94CO2CH2CH2CH3. In the most preferred embodiments, Ra, Rb and Rc are each hydrogen.
Also preferred at Ra, Rb and Rc is the group xe2x80x94CO2Rw, where Rw is one of 
where Rd-Rh are defined as above. When Ra, Rb and Rc are xe2x80x94CO2Rw, where Rw is one of these moieties, the resulting compounds are prodrugs that possess desirable formulation and bioavailability characteristics. A preferred value for each of Rd, Re and Rf is hydrogen, Rf is methyl, and preferred values for Rh include benzyl and tert-butyl.
Preferred values of m, mxe2x80x2, n, nxe2x80x2, j, and jxe2x80x2 in Formulae Ia and Ib are 0 or 1, provided that m, mxe2x80x2, n, nxe2x80x2, j, and jxe2x80x2 are not all zero. The most preferred value for each n, nxe2x80x2, j, jxe2x80x2, and m is 1; the most preferred value for mxe2x80x2 is zero.
Compounds of the present invention also include compounds of Formula II: 
or a solvate, hydrate or pharmaceutically acceptable salt thereof; wherein:
A is one of 
Thus, the compounds of Formula II are represented by Formulae IIa and IIb: 
or a solvate, hydrate or pharmaceutically acceptable salt thereof.
For each of Formulae II, IIa and IIb, the following values apply:
L represents xe2x80x94C(O)xe2x80x94, C(R2YR2Z), or xe2x80x94SO2xe2x80x94;
R2Y and R2Z are each independently one of hydrogen, alkyl, cycloalkyl, aryl, aralkyl, hydroxyalkyl, carboxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl or carboxy;
R21 represents a group: 
R22 represents a group: 
or R21 and R22 can be taken together with the nitrogen atom to which they are attached to form a three to seven membered ring, either of which contains an additional nitrogen or oxygen atom, and which is optionally benzo- or pyrido-fused, said ring being preferably saturated, and said ring having one or two optional substituents on either a ring carbon or nitrogen selected from the group consisting of halogen, hydroxy, acyloxy, alkoxy, aryloxy, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroar(C1-4)alkyl, carboxyalkyl, alkoxycarbonylalkyl, hydroxyalkoxyalkyl, cyano(C2-10)alkyl, hydroxy(C2-10)alkyl, alkoxy(C2-10)alkyl, alkoxyalkyl, mono- and di-alkylamino(C2-10)alkyl, carboxy, alkoxycarbonyl, carboxamido, formyl, alkanoyl, aroyl, aralkanoyl, sulfonyl, alkylsulfonyl, alkoxysulfonyl, and NR13R14 (when C-substituted);
R12 and R12xe2x80x2 independently represent hydrogen, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-7 heterocycloalkyl, C3-7 heterocycloalkenyl, aryl, or heteroaryl, which groups are optionally substituted with C1-6 alkyl or hydroxy, or R12 and R12xe2x80x2 independently represent diarylmethyl, diheteroarylmethyl, dicycloalkylmethyl or (aryl)(heteroaryl)CHxe2x80x94;
Q and Qxe2x80x2 independently represent a bond, a C1-6 alkyl chain, a C3-6 alkenyl chain, or a C3-6 alkynyl chain, where one or two nitrogen, oxygen, or sulfur atoms may be optionally contained within each chain, and the chains are optionally substituted by one or more groups selected from halogen, hydroxy, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxy(C1-6)alkyl, C1-6 acyloxy, NR13R14, NHCOR15, NHSO2R16, COR15, CO2R15, CONR13R14, and SO2NR17R18;
R13-R16 represent hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, mono- or di-hydroxy(C6-10)aryl, C6-10 ar(C1-4)alkyl, pyridyl, pyridyl(C1-4)alkyl, carboxy(C1-6)-alkyl, C1-4 alkoxycarbonyl(C1-4)alkyl, cyano(C2-6)alkyl, hydroxy(C2-6)alkyl, C1-4 alkoxy(C2-6)alkyl, mono- and di-(C1-4)alkylamino(C2-6)alkyl;
or R13 and R14 form a C3-7 heterocycloalkyl ring,
or R16 additionally may represent trifluoromethyl;
R17 and R18 are independently selected from the group consisting of hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C6-10 ar(C1-4)alkyl, pyridyl, pyridyl(C1-4)alkyl, carboxy(C1-6)alkyl, C1-4 alkoxycarbonyl-(C1-4)alkyl, cyano(C2-6)alkyl, hydroxy(C2-6)alkyl, C1-4 alkoxy(C2-6)alkyl, and mono- and di-(C1-4)alkylamino(C2-6)alkyl,
or R17 and R18 can be taken together with the nitrogen atom to which they are attached to form a heterocyclic ring selected from the group consisting of N-morpholino, N-piperazinyl (optionally Nxe2x80x2 substituted with C1-6 alkyl, C1-6 hydroxyalkyl, C6-10 aryl, C6-10 aryl(C1-6)alkyl, C1-6 alkylsulfonyl, C6-10 arylsulfonyl, C1-6 alkylcarbonyl, morpholino or C6-10 arylcarbonyl), N-pyrrolyl, N-piperidinyl, N-pyrrolidinyl, N-dihydropyridyl, and N-indolyl, wherein said heterocyclic ring can be optionally C-substituted.
R23, R24, R25 and R26 are each independently one of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, trifluoromethyl, halogen, hydroxyalkyl, cyano, nitro, carboxamido, xe2x80x94CO2Rx, xe2x80x94CH2ORx or xe2x80x94ORx, or when present on adjacent carbon atoms, R23 and R24 may also be taken together to form one of xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94 or xe2x80x94(CH2)qxe2x80x94, where q is from 2 to 6, and R25 and R26 are defined as above;
Rx, in each instance, is independently one of hydrogen, alkyl or cycloalkyl wherein said alkyl or cycloalkyl groups may optionally have one or more unsaturations;
Y is one of xe2x80x94Oxe2x80x94, xe2x80x94NR19xe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94CHR19xe2x80x94 or a covalent bond;
R19, in each instance, is independently hydrogen, C1-6 alkyl, benzyl, phenyl, C2-10 hydroxyalkyl, C2-10 aminoalkyl, C1-4 monoalkylamino(C2-8)alkyl, C1-4 dialkylamino(C2-8)alkyl or C2-10 carboxyalkyl;
Ra, Rb and Rc are independently hydrogen, alkyl, hydroxy, alkoxy, aryloxy, aralkoxy, alkoxycarbonyloxy, cyano or xe2x80x94CO2Rw, where
Rw is alkyl, cycloalkyl, phenyl, benzyl, 
xe2x80x83where Rd and Re are independently hydrogen, C1-6 alkyl, C2-6 alkenyl or phenyl, Rf is hydrogen, C1-6 alkyl, C2-6 alkenyl or phenyl, Rg is hydrogen, C1-6 alkyl, C2-6 alkenyl or phenyl, and Rh is aralkyl or C1-6 alkyl;
n and nxe2x80x2 are each from zero to 4, preferably zero to 2;
m and mxe2x80x2 are each from zero to 4, preferably zero to 2; and
j and jxe2x80x2 are each from zero to 4, preferably zero to 2;
provided that n, nxe2x80x2, m, mxe2x80x2, j, and jxe2x80x2 are not all zero.
Preferred values of Ra, Rb, Rc, m, mxe2x80x2, n, nxe2x80x2, j, and jxe2x80x2 in Formulae IIa and IIb are the same as those defined for Formulae Ia and Ib above.
Referring to Formulae IIa and IIb, where R22 represents a group 
Qxe2x80x2 is suitably C3-6 alkenyl, e.g., alkyl, or C1-6 alkyl, e.g., methyl, ethyl, propyl or pentyl, which optionally contains an oxygen group within the chain and is optionally substituted by a group selected from hydroxy, C1-6 alkoxy, NHSO2R16, CO2R15, CONR13R14, or SO2NR17R18, and R12xe2x80x2 is suitably hydrogen, C3-7 heterocycloalkyl, e.g., pyrrolidine or morpholine, aryl, e.g., phenyl which is optionally substituted by CO2R15, or heteroaryl, e.g., oxadiazole optionally substituted by hydroxy, triazole, or tetrazole optionally substituted by C1-6 alkyl. Referring to the general Formulae IIa and IIb, where R21 represents a group 
Q is suitably a bond or C1-6 alkyl group, e.g., methyl, isopropyl or isobutyl, and R12 suitably represents hydrogen, C3-7 cycloalkyl, aryl, or heteroaryl. When Q represents a bond, R12 is preferably optionally substituted phenyl, C3-7 cycloalkyl, e.g., cyclobutyl, cyclopentyl or cyclohexyl, diphenylmethyl or dicyclohexylmethyl. When Q represents a C1-4 alkyl group, R12 is preferably hydrogen, cycloalkyl, e.g., cyclohexyl, or heteroaryl, e.g., thienyl or furyl.
Particularly preferred combinations of R21 and R22 include:
(A) R21 and R22 are taken together with the nitrogen to which they are attached to form a C3-7 heterocycloalkyl or C3-7 heterocycloalkenyl group, optionally benzo fused and optionally including an oxygen atom or an additional nitrogen atom, and which may be optionally substituted by C1-6 alkyl, hydroxy, C1-4 alkoxy, C2-6 alkoxycarbonyl, formyl, (C6-10)ar(C1-4)alkyl, C6-10 aryl, pyridyl, hydroxyalkoxyalkyl, halogen, or NR13R14; or
(B) R21 is C3-7 cycloalkyl or C3-7 cycloalkenyl, either of which is optionally substituted by C1-6 alkyl, hydroxy, C1-4 alkoxy, halogen, carboxylic acid, a C1-4 carboxylic acid ester group, or NR13R14, and R22 is C3-6 alkenyl, or C3-6 alkynyl, either of which is optionally substituted by C1-6 alkyl, hydroxy, C1-4 alkoxy, halogen, carboxylic acid, a C1-4 carboxylic acid ester group, or NR13R14; or
(C) R21 is C3-7 heterocycloalkyl(C1-6)alkyl, C3-7 heterocycloalkenyl(C1-6)alkyl, heteroaryl(C1-6)alkyl, C3-7 heterocycloalkyl(C3-6)alkenyl, C3-7 heterocycloalkenyl(C3-6)alkenyl, heteroaryl(C3-6)alkenyl, C3-7 heterocycloalkyl(C3-6)alkynyl, C3-7 heterocycloalkenyl(C3-6)alkynyl, heteroaryl(C3-6)alkynyl, di(C5-10 aryl)(C1-3)alkyl, di(C3-8 cycloalkyl)(C1-3)alkyl or di(C3-8 cycloalkenyl)(C1-3)alkyl, any of which is optionally substituted by C1-6 alkyl, hydroxy, C1-4 alkoxy, halogen, carboxylic acid, a C1-4 carboxylic acid ester group, or NR13R14; and
R22 is a group 
where R12xe2x80x2 and Qxe2x80x2 have the values and preferred values defined above.
R23 can represent hydrogen, C1-3 alkyl, halogen, or C1-2 alkoxy. R23 is preferably C1-3 alkyl, e.g., methyl, or halogen, e.g., chlorine or bromine.
R24, R25, and R26 can independently represent hydrogen, or halogen. R24, R25, and R26 are preferably hydrogen, or halogen, e.g., fluorine.
Preferred values of Y are divalent oxygen (xe2x80x94Oxe2x80x94), xe2x80x94NR19xe2x80x94 or a covalent bond, most preferably xe2x80x94Oxe2x80x94.
Preferred values of R19 are hydrogen, C1-6 alkyl and C3-6 cycloalkyl.
Specific compounds within the scope of the invention include the following:
3-[(2-amidino(1,2-oxazaperhydroin-5-yl))methoxy]-5-methylphenyl 2-(methylsulfonyl)benzenesulfonate;
3-[(2-amidino(1,2-oxazaperhydroin-5-yl))methoxy]-5-chlorophenyl 2-(methylsulfonyl)benzenesulfonate;
3-[(2-amidino(1,2-oxazaperhydroin-5-yl))methoxy]-5-methylphenyl 2-(methoxy)benzenesulfonate;
3-[(2-amidino(1,2-oxazaperhydroin-5-yl))methoxy]-5-methylphenyl quinolinyl-8-sulfonate;
3-[(2-amidino(1,2-oxazaperhydroin-5-yl))methoxy]-5-methylphenyl 5-chloro-2-(methoxy)benzenesulfonate;
3-[(2-amidino(1,2-oxazaperhydroin-5-yl))methoxy]-5-methylphenyl 5-chlorothiophenyl-2-sulfonate;
3-[(2-amidino(1,2-oxazaperhydroin-5-yl))methoxy]-5-methylphenyl 2-cyanobenzenesulfonate;
3-[(2-amidino(1,2-oxazaperhydroin-5-yl))methoxy]-5-methylphenyl 2-(methylsulfonyl)benzenesulfonate;
3-[(2-amidino(1,2-oxazaperhydroin-5-yl))methoxy]-5-methylphenyl 2-(morpholinylsulfonyl)benzenesulfonate;
3-[(2-amidino(1,2-oxazaperhydroin-5-yl))methoxy]-5-methylphenyl 2-(N-methylphenethylaminosulfonyl)benzenesulfonate;
3-[(2-amidino(1,2-oxazaperhydroin-5-yl))methoxy]-5-methylphenyl 2-[(4-ethyloxycarbonyl)piperidinylsulfonyl]benzenesulfonate;
3-[(2-amidino(1,2-oxazaperhydroin-5-yl))methoxy]-5-methylphenyl 3-[(2,4-bis(methylsulfonyl)]benzenesulfonate;
3-[(2-amidino(1,2-oxazaperhydroin-5-yl))methoxy]-5-methylphenyl 6-[(2,3-dihydro-1,1-dioxobenzo[b]thiophene)]benzenesulfonate;
3-[(2-amidino(1,2-oxazaperhydroin-5-yl))methoxy]-5-methylphenyl 2-[(4-biphenylmethoxy)]benzenesulfonate;
3-[(2-amidino(1,2-oxazaperhydroin-5-yl))methoxy]-5-methylphenyl N-ethyl-3,4-[(methylenedioxy)anilinosulfonyl]benzenesulfonate;
3-[(2-amidino(1,2-oxazaperhydroin-5-yl))methoxy]-5-methylphenyl 3-ethoxycarbonyl-1-(piperidinosulfonyl)benzenesulfonate;
3-[(2-amidino(1,2-oxazaperhydroin-5-yl))methoxy]-5-methylphenyl 2-methoxycarbonyl-1-pyrrolidinosulfonyl-benzenesulfonate;
3-[(2-amidino(1,2-oxazaperhydroin-5-yl))methoxy]-5-methylphenyl 2-(N-propyl-N-(2-(2-pyridyl)ethyl)aminosulfonyl)benzenesulfonate;
3-[(2-amidino(1,2-oxazaperhydroin-5-yl))methoxy]-5-methylphenyl 2-(N,N-bis-(2-cyanoethyl)aminosulfonyl)benzenesulfonate;
3-[(2-amidino(1,2-oxazaperhydroin-5-yl))methoxy]-5-methylphenyl 2-(N-(2-carboxyethyl)-N-benzylaminosulfonyl)benzenesulfonate;
3-[(2-amidino(1,2-oxazaperhydroin-5-yl))methoxy]-5-methylphenyl 2-(4-(carboxymethyl)piperazin-N-1-ylsulfonyl)benzenesulfonate;
3-[(2-amidino(1,2-oxazaperhydroin-5-yl))methoxy]-5-methylphenyl 2-(N-(2-cyanoethyl)-N-(2-furanylmethyl) aminosulfonyl)benzenesulfonate;
3-[(2-amidino(1,2-oxazaperhydroin-5-yl))methoxy]-5-methylphenyl 2-(N-ethyl-N-(1-benzyl-3-pyrrolidinyl)aminosulfonyl)benzenesulfonate;
5-{[5-chloro-3-(N-cyclopentyl-N-prop-2-enylcarbamoyl)phenoxy]methyl}-1,2-oxazaperhydroine-2-carboxamidine;
5-{[5-chloro-3-(4-benzylpiperidinylcarbonyl)phenoxy]methyl}-1,2-oxazaperhydroine-2-carboxamidine;
5-{[5-chloro-3-(N,N-bis[2-methoxyethyl]aminocarbonyl)phenoxy]methyl}-1,2-oxazaperhydroine-2-carboxamidine;
5-{[5-chloro-3-(N-methyl-N-[3-pyridylmethyl]-aminocarbonyl)phenoxy]methyl}-1,2-oxazaperhydroine-2-carboxamidine;
5-{[5-chloro-3-(N-[2-m dimethylamino ethyl]-N-ethylaminocarbonyl)phenoxy]methyl}-1,2-oxazaperhydroine-2-carboxamidine;
5-{[5-chloro-3-(4-formylpiperazinylcarbonyl)phenoxy]methyl}-1,2-oxazaperhydroine-2-carboxamidine;
5-{[5-chloro-3-(4-benzylpiperazinylcarbonyl)phenoxy]methyl}-1,2-oxazaperhydroine-2-carboxamidine;
5-{[5-chloro-3-(2-[1,2,3,4-tetrahydro]-isoquinolinylcarbonyl)phenoxy]methyl}-1,2-oxazaperhydroine-2-carboxamidine;
5-{[5-chloro-3-(azaperhydroepinylcarbonyl)phenoxy]methyl}-1,2-oxazaperhydroine-2-carboxamidine;
as well as pharmaceutically acceptable salts thereof, for example the hydrochloride, acetate, and trifluoroacetate salts thereof. Structures for these compounds are provided in the pages prior to the claims.
It is also to be understood that the present invention is considered to include stereoisomers as well as optical isomers, e.g. mixtures of enantiomers, as well as individual enantiomers and diastereomers, which arise as a consequence of structural asymmetry in selected compounds of the present series.
The compounds of Formulae I and II may also be solvated, especially hydrated. Hydration may occur during manufacturing of the compounds or compositions comprising the compounds, or the hydration may occur over time due to the hygroscopic nature of the compounds.
Certain compounds within the scope of Formulae I and II are derivatives referred to as prodrugs. The expression xe2x80x9cprodrugxe2x80x9d denotes a derivative of a known direct acting drug, which derivative has enhanced delivery characteristics and therapeutic value as compared to the drug, and is transformed into the active drug by an enzymatic or chemical process; see Notari, R. E., xe2x80x9cTheory and Practice of Prodrug Kinetics,xe2x80x9d Methods in Enzymology, 112:309-323 (1985); Bodor, N., xe2x80x9cNovel Approaches in Prodrug Design,xe2x80x9d Drugs of the Future, 6(3):165-182 (1981); and Bundgaard, H., xe2x80x9cDesign of Prodrugs: Bioreversible-Derivatives for Various Functional Groups and Chemical Entities,xe2x80x9d in Design of Prodrugs (H. Bundgaard, ed.), Elsevier, N.Y. (1985). Useful prodrugs are those where Ra, Rb and/or Rc are xe2x80x94CO2Rw, where Rw is defined above. See, U.S. Pat. No. 5,466,811 and Saulnier et al., Bioorg. Med. Chem. Lett. 4:1985-1990 (1994).
When any variable occurs more than one time in any constituent or in Formulae I and II, its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
The term xe2x80x9calkylxe2x80x9d as employed herein by itself or as part of another group refers to both straight and branched chain radicals of up to 12 carbons, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl. Preferred alkyl groups have 1 to 6 carbon atoms.
The term xe2x80x9calkenylxe2x80x9d is used herein to mean a straight or branched chain radical of 2-20 carbon atoms, unless the chain length is limited thereto, including, but not limited to, ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like. Preferably, the alkenyl chain is 2 to 10 carbon atoms in length, more preferably, 2 to 8 carbon atoms in length most preferably from 2 to 4 carbon atoms in length.
The term xe2x80x9calkynylxe2x80x9d is used herein to mean a straight or branched chain radical of 2-20 carbon atoms, unless the chain length is limited thereto, wherein there is at least one triple bond between two of the carbon atoms in the chain, including, but not limited to, acetylene, 1-propylene, 2-propylene, and the like. Preferably, the alkynyl chain is 2 to 10 carbon atoms in length, more preferably, 2 to 8 carbon atoms in length, most preferably from 2 to 4 carbon atoms in length.
In all instances herein where there is an alkenyl or alkynyl moiety as a substituent group, the unsaturated linkage, i.e., the vinylene or acetylene linkage is preferably not directly attached to a nitrogen, oxygen or sulfur moiety.
The term xe2x80x9calkoxyxe2x80x9d is used herein to mean a straight or branched chain radical of 1 to 20 carbon atoms, unless the chain length is limited thereto, bonded to an oxygen atom, including, but not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and the like. Preferably the alkoxy chain is 1 to 10 carbon atoms in length, more preferably 1 to 8 carbon atoms in length.
The term xe2x80x9carylxe2x80x9d as employed herein by itself or as part of another group refers to monocyclic or bicyclic aromatic groups containing from 6 to 12 carbons in the ring portion, preferably 6-10 carbons in the ring portion, such as phenyl, naphthyl or tetrahydronaphthyl.
The term xe2x80x9cheteroarylxe2x80x9d as employed herein refers to groups having 5 to 14 ring atoms; 6, 10 or 14 xcfx80 electrons shared in a cyclic array; and containing carbon atoms and 1, 2 or 3 oxygen, nitrogen or sulfur heteroatoms (where examples of heteroaryl groups are: thienyl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl, pyranyl, isobenzofuranyl, benzoxazolyl, chromenyl, xanthenyl, phenoxathiinyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinazolinyl, cinnolinyl, pteridinyl, 4xcex1H-carbazolyl, carbazolyl, xcex2-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl, furazanyl and phenoxazinyl groups).
The term xe2x80x9caralkylxe2x80x9d or xe2x80x9carylalkylxe2x80x9d as employed herein by itself or as part of another group refers to C1-6alkyl groups as discussed above having an aryl substituent, such as benzyl, phenylethyl or 2-naphthylmethyl.
The term xe2x80x9ccycloalkylxe2x80x9d as employed herein by itself or as part of another group refers to cycloalkyl groups containing 3 to 9 carbon atoms. Typical examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and cyclononyl.
The terms xe2x80x9calkoxyxe2x80x9d refers to any of the above alkyl groups linked to an oxygen atom.
The term xe2x80x9chalogenxe2x80x9d or xe2x80x9chaloxe2x80x9d as employed herein by itself or as part of another group refers to chlorine, bromine, fluorine or iodine with chlorine being preferred.
The term xe2x80x9cmonoalkylaminexe2x80x9d as employed herein by itself or as part of another group refers to an amino group which is substituted with one alkyl group having from 1 to 6 carbon atoms.
The term xe2x80x9cdialkylaminexe2x80x9d as employed herein by itself or as part of another group refers to an amino group which is substituted with two alkyl groups, each having from 1 to 6 carbon atoms
The term xe2x80x9chydroxyalkylxe2x80x9d as employed herein refers to any of the above alkyl groups substituted by one or more hydroxyl moieties.
The term xe2x80x9ccarboxyalkylxe2x80x9d as employed herein refers to any of the above alkyl groups substituted by one or more carboxylic acid moieties.
The term xe2x80x9cheterocyclicxe2x80x9d is used herein to mean a saturated or wholly or partially unsaturated 3-7 membered monocyclic, or 7-10 membered bicyclic ring system, which consists of carbon atoms and from one to four heteroatoms independently selected from the group consisting of O, N, and S, wherein the nitrogen and sulfur heteroatoms can be optionally oxidized, the nitrogen can be optionally quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring, and wherein the heterocyclic ring can be substituted on carbon or on a nitrogen atom if the resulting compound is stable. Especially useful are rings containing one oxygen or sulfur, one to three nitrogen atoms, or one oxygen or sulfur combined with one or two nitrogen atoms. Examples of such heterocyclic groups include piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazoyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, and oxadiazolyl. Morpholino is the same as morpholinyl.
The term xe2x80x9cheteroatomxe2x80x9d is used herein to mean an oxygen atom (xe2x80x9cOxe2x80x9d), a sulfur atom (xe2x80x9cSxe2x80x9d) or a nitrogen atom (xe2x80x9cNxe2x80x9d). It will be recognized that when the heteroatom is nitrogen, it may form an NRyRz moiety, wherein Ry and Rz are, independently from one another, hydrogen or C1 to C8 alkyl, or together with the nitrogen to which they are bound, form a saturated or unsaturated 5-, 6-, or 7-membered ring.
The compounds of the present invention may be prepared by the general procedures outlined in Schemes I, II, and III where R1-R6, R21-R26, Ra, Rb, Rc, n, m, and j are as defined above. Pa is an ester protecting group, such as ethyl or methyl; Pb, Pc, and Pe are hydroxyl protecting groups, such as tert-butyldimethylsilyl and triisopropylsilyl; Pd is an amino protecting group, such as tert-butoxycarbonyl (Boc) and benzyloxycarbonyl (Cbz). The schemes illustrate but are not limited to the preparation of the compounds of Examples 1 to 3. 
Scheme I outlines the synthetic steps to produce cyclic oxyamine 7, a precursor of cyclic oxyguanidine. Diethyl malonate 1 [Pa=ethyl] is deprotonated by treatment with a mild base, such as sodium ethoxide, to form an enolate in a polar protic solvent such as ethyl alcohol. This carbanion subsequently reacts with an alkylating reagent 2, where L is a reactive leaving group, such as a halide, to produce a monoalkylated compound 3. The ester groups of 3 are reduced with a reducing agent, such as lithium borohydride, in a suitable solvent, such as tetrahydrofuran, to give a diol (n, m=1). This symmetric diol is then monoprotected as a silyl ether by reacting with one equivalent of base such as sodium hydride in an appropriate solvent, such as tetrahydrofuran, followed by monosilylation with one equivalent of triisopropylsilyl chloride or other related reagents. Alcohol 4 is converted to 5 employing a Mitsunobu reaction with a N-hydroxycyclic imide derivative such as N-hydroxyphthalimide. Preferred reaction conditions include using a trialkylphosphine or triarylphosphine, such as tri-n-butylphosphine or triphenylphosphine, in a suitable solvent, such as tetrahydrofuran, and an azodicarbonyl reagent, such as diethyl azodicarboxylate or 1,1xe2x80x2-(azodicarbonyl)dipiperidine.
Selective deprotection of trialkylsilyl group Pb (Pb=tert-butyldimethylsilyl) of 5 in the presence of another hydroxyl protecting group Pc (Pc=triisopropylsilyl) is achieved by using an acid, such as fluorosilicic acid, in a suitable solvent system, such as 2-methyl-2-propanol and water. Unveiling of the phthalimide protecting group of 5 is accomplished using standard conditions well known in the art (Greene, T. W. and Wuts, P. G. M., Protective Groups in Organic Synthesis, 3rd edition, John Wiley and Sons, Inc. New York (1999)), for example, using hydrazine or methylamine, or alternatively, sodium borohydride in a mixture of an appropriate alcohol (e.g., ethanol/water) followed by acidification. The released primary amine is then converted to carbamate 6, such as tert-butoxycarbamate, in a biphasic system composed of an organic solvent, such as dichloromethane, and a basic aqueous phase saturated with sodium bicarbonate. Intramolecular cyclization of 6 occurs to give a cyclic oxyamine under the standard Mitsunobu condition, i.e. using triphenylphosphine and diethyl azodicarboxylate in tetrahydrofuran. Deprotection of the hydroxyl protecting group Pc is routinely accomplished using the conventional conditions. For example, triisopropylsilyl may be removed by reacting with tetrabutylammonium fluoride in tetrahydrofuran. 
Scheme II outlines the synthetic steps to produce compounds of the present invention where Z of Formula I is SO2, and Yxe2x95x90O. Phenol 8 is converted to monosulfonate 9 by reacting with appropriate sulfonyl chlorides. Preferred conditions include treating phenol 8 with a sulfonyl chloride in a biphasic system composed of an organic solvent, such as diethyl ether or dichloromethane, and an aqueous phase saturated with NaHCO3. Alternatively, the conversion may be effected by first deprotonating 8 with one equivalent of a strong base, most preferably sodium hydride, in a polar solvent, such as N,N-dimethylformamide or tetrahydrofuran, followed by treating the phenoxyl anion with sulfonyl chlorides. Still alternatively, phenol 8 in a typical organic solvent, such as dichloromethane, may be converted to 9 by treating the phenol with sulfonyl chlorides in the presence of an amine base, such as 4-methylmorpholine.
Phenol 9 is coupled with 7 using a Mitsunobu procedure (Mitsunobu, O., Synthesis 1, (1981)), i.e. in the presence of triphenylphosphine and diethyl azodicarboxylate in tetrahydrofuran. Deprotection of the oxyamino protecting group Pd of 10 is routinely accomplished using conventional conditions. For example, tert-butyloxycarbonyl (Boc) maybe removed in an acidic solution, such as trifluoroacetic acid in dichloromethane. Guanidinylation of the resulting cyclic O-amine may be achieved using standard reagents such as aminoiminosulfonic acid (Miller, A. E. and Bischoff, J. J., Synthesis 777 (1986)), or 1H-pyrazole-1-carboxamidine hydrochloride (Bernatowicz, M. S. et al., J. Org. Chem. 57(8):2497 (1992)), or substituted guanidinylating reagents such as N,Nxe2x80x2-bis(tert-butoxycarbonyl)-S-methylisothiourea (Bergeron, R. J. and McManis, J. S., J. Org. Chem. 52:1700 (1987)) or Nxe2x80x94Ra, Nxe2x80x94Rb-1H-pyrazole-1-carboxamdine, where Ra and Rb are defined as above for Formula I. When Ra and Rb are protecting groups, for example t-butyloxycarbonyl (Boc), compound 11 can be optionally reacted with RcOH using the standard Mitsunobu reaction condition as reviewed above to produce alkylated compound 12. These protecting groups can be optionally removed by treatment with acid, usually trifluoroacetic acid in a suitable solvent such as dichloromethane or water, or HCl gas dissolved in a suitable solvent, such as 1,4-dioxane to produce compound 13. 
Scheme III outlines the synthetic step to produce compounds of the present invention where L of Formula II is Cxe2x95x90O and Yxe2x95x90O. Thus, halogenated phenol 14 may be protected with a variety of protecting groups well known in the art, such as trialkylsilyl ethers, alkyl ethers, or esters (Greene, T. W., Wuts, P. G. M., Protective Groups in Organic Synthesis, 3rd edition, John Wiley and Sons, Inc. New York (1999)). The protected chloro-substituted compound is transformed to benzoic acid 15 by reacting with Rieke magnesium in a suitable solvent, such as diethyl ether or tetrahydrofuran, to form a Grignard intermediate which is then quenched with carbon dioxide. In the presence of a coupling reagent, such as 1,3-dicyclohexylcarbodiimide or Castro""s reagent (BOP) (Castro, B., et al., Tetrahedron Letter 1219 (1975)), the benzoic acid 15 is reacted with amines to generate amides. The protecting group Pe is removed under standard reaction conditions. When the protecting group Pe is tert-butyldimethysilyl, the preferred condition involving using tetrabutylammonium fluoride in tetrahydrofuran to give phenol 16.
Phenol 16 is coupled with 7 using a Mitsunobu procedure (Mitsunobu, O., Synthesis 1, (1981)), i.e. in the presence of triphenylphosphine and diethyl azodicarboxylate in tetrahydrofuran. Deprotection of the oxyamino protecting group Pd of 17 is routinely accomplished using conventional conditions. For example, tert-butyloxycarbonyl (Boc) may be removed in an acidic solution, such as trifluoroacetic acid in dichloromethane. Guanidinylation of the resulting cyclic O-amine may be achieved using standard reagents such as aminoiminosulfonic acid (Miller, A. E. and Bischoff, J. J., Synthesis 777 (1986)), or 1H-pyrazole-1-carboxamidine hydrochloride (Bernatowicz, M. S. et al., J. Org. Chem. 57(8):2497 (1992)), or substituted guanidinylating reagents such as N,Nxe2x80x2-bis(tert-butoxycarbonyl)-S-methylisothiourea (Bergeron, R. J. and McManis, J. S., J. Org. Chem. 52:1700 (1987)) or Nxe2x80x94Ra, Nxe2x80x94Rb-1H-pyrazole-1-carboxamidine, where Ra and Rb are defined as above for Formula II. When Ra and Rb are protecting groups, for example t-butyloxycarbonyl (Boc), compound 18 can be optionally reacted with RcOH using the standard Mitsunobu reaction condition as reviewed above to produce alkylated compound 19. These protecting groups can be optionally removed by treatment with acid, usually trifluoroacetic acid in a suitable solvent such as dichloromethane or water, or HCl gas dissolved in a suitable solvent, such as 1,4-dioxane to produce compound 20.
The compounds of the present invention represent a novel class of potent inhibitors of metallo, acid, thiol and serine proteases. Examples of the serine proteases inhibited by compounds within the scope of the invention include leukocyte neutrophil elastase, a proteolytic enzyme implicated in the pathogenesis of emphysema; chymotrypsin and trypsin, digestive enzymes; pancreatic elastase, and cathepsin G, a chymotrypsin-like protease also associated with leukocytes; thrombin and factor Xa, proteolytic enzymes in the blood coagulation pathway. Inhibition of thermolysin, a metalloprotease, and pepsin, an acid protease, are also contemplated uses of compounds of the present invention. The compounds of the present invention are preferably employed to inhibit trypsin-like proteases.
An end use application of the compounds that inhibit chymotrypsin and trypsin is in the treatment of pancreatitis. For their end-use application, the potency and other biochemical parameters of the enzyme-inhibiting characteristics of the compounds of the present invention is readily ascertained by standard biochemical techniques well known in the art. Actual dose ranges for their specific end-use application will, of course, depend upon the nature and severity of the disease state of the patient or animal to be treated, as determined by the attending diagnostician. It is expected that a useful dose range will be about 0.01 to 10 mg per kg per day for an effective therapeutic effect.
Compounds of the present invention that are distinguished by their ability to inhibit either factor Xa or thrombin may be employed for a number of therapeutic purposes. As factor Xa or thrombin inhibitors, compounds of the present invention inhibit thrombin production. Therefore, these compounds are useful for the treatment or prophylaxis of states characterized by abnormal venous or arterial thrombosis involving either thrombin production or action. These states include, but are not limited to, deep vein thrombosis; disseminated intravascular coagulopathy which occurs during septic shock, viral infections and cancer; myocardial infarction; stroke; coronary artery bypass; fibrin formation in the eye; hip replacement; and thrombus formation resulting from either thrombolytic therapy or percutaneous transluminal coronary angioplasty (PCTA). Other uses include the use of said thrombin inhibitors as anticoagulants either embedded in or physically linked to materials used in the manufacture of devices used in blood collection, blood circulation, and blood storage, such as catheters, blood dialysis machines, blood collection syringes and tubes, blood lines and stents. The compounds of the present invention may also be used as an anticoagulant in extracorporeal blood circuits.
Metal stents have been shown to reduce restenosis, but are thrombogenic. A strategy for reducing the thrombogenicity of stents is to coat, embed, adsord or covalently attach a thrombin-inhibiting agent to the stent surface. The compounds of the present invention can be employed for this purpose. Compounds of the invention can be attached to, or embedded within soluble and/or biodegradeable polymers as and thereafter coated onto stent materials. Such polymers can include polyvinylpyrrolidone, polyhydroxy-propyl-methacrylamide-phenol, polyhydroxyethyl-aspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross linked or amphipathic block copolymers of hydrogels. See European Application 761 251, European Application 604,022, Canadian Patent 2,164,684 and PCT Published Applications WO 96/11668, WO 96/32143 and WO 96/38136.
By virtue of the effects of both factor Xa and thrombin on a host of cell types, such as smooth muscle cells, endothelial cells and neutrophils, the compounds of the present invention find additional use in the treatment or prophylaxis of adult respiratory distress syndrome; inflammatory responses; wound healing; reperfusion damage; atherosclerosis; and restenosis following an injury such as balloon angioplasty, atherectomy, and arterial stent placement. The compounds of the present invention may be useful in treating neoplasia and metastasis as well as neurodegenerative diseases, such as Alzheimer""s disease and Parkinson""s disease.
When employed as thrombin or factor Xa inhibitors, the compounds of the present invention may be administered in an effective amount within the dosage range of about 0.1 to about 500 mg/kg, preferably between 0.1 to 10 mg/kg body weight, on a regimen in single or 2-4 divided daily doses.
When employed as inhibitors of thrombin, the compounds of the present invention may be used in combination with thrombolytic agents such as tissue plasminogen activator, streptokinase, and urokinase. Additionally, the compounds of the present invention may be used in combination with other antithrombotic or anticoagulant drugs such as, but not limited to, fibrinogen antagonists and thromboxane receptor antagonists.
Human leucocyte elastase is released by polymorphonuclear leukocytes at sites of inflammation and thus is a contributing cause for a number of disease states. Compounds of the present invention are expected to have an anti-inflammatory effect useful in the treatment of gout, rheumatoid arthritis and other inflammatory diseases, and in the treatment of emphysema. The leucocyte elastase inhibitory properties of compounds of the present invention are determined by the method described below. Cathepsin G has also been implicated in the disease states of arthritis, gout and emphysema, and in addition, glomerulonephritis and lung infestations caused by infections in the lung. In their end-use application the enzyme inhibitory properties of the compounds of Formulae I and II is readily ascertained by standard biochemical techniques that are well-known in the art.
The Cathepsin G inhibitory properties of compounds within the scope of the present invention are determined by the following method. A preparation of partially purified human Cathepsin G is obtained by the procedure of Baugh et al., Biochemistry 15: 836 (1979). Leukocyte granules are a major source for the preparation of leukocyte elastase and cathepsin G (chymotrypsin-like activity). Leukocytes are lysed and granules are isolated. The leukocyte granules are extracted with 0.20 M sodium acetate, pH 4.0, and extracts are dialyzed against 0.05 M Tris buffer, pH 8.0 containing 0.05 M NaCl overnight at 4xc2x0 C. A protein fraction precipitates during dialysis and is isolated by centrifugation. This fraction contains most of the chymotrypsin-like activity of leukocyte granules. Specific substrates are prepared for each enzyme, namely N-Suc-Ala-Ala-Pro-Val-p-nitroanilide and Suc-Ala-Ala-Pro-Phe-p-nitroanilide. The latter is not hydrolyzed by leukocyte elastase. Enzyme preparations are assayed in 2.00 mL of 0.10 M Hepes buffer, pH 7.5, containing 0.50 M NaCl, 10% dimethylsulfoxide and 0.0020 M Suc-Ala-Ala-Pro-Phe-p-nitroanilide as a substrate. Hydrolysis of the p-nitroanilide substrate is monitored at 405 nm and at 25xc2x0 C.
Useful dose range for the application of compounds of the present invention as neutrophil elastase inhibitors and as Cathepsin G inhibitors depend upon the nature and severity of the disease state, as determined by the attending diagnostician, with a range of 0.01 to 10 mg/kg body weight, per day, being useful for the aforementioned disease states.
Compounds of the present invention that inhibit urokinase or plasminogen activator are potentially useful in treating excessive cell growth disease state. As such compounds of the present invention may also be useful in the treatment of benign prostatic hypertrophy and prostatic carcinoma, the treatment of psoriasis, and as abortifacients. For their end-use application, the potency and other biochemical parameters of the enzyme inhibiting characteristics of compounds of the present invention are readily ascertained by standard biochemical techniques well known in the art. Actual dose ranges for this application will depend upon the nature and severity of the disease state of the patient or animal to be treated as determined by the attending diagnostician. It is to be expected that a general dose range will be about 0.01 to 10 mg per kg per day for an effective therapeutic effect.
Additional uses for compounds of the present invention include analysis of commercial reagent enzymes for active site concentration. For example, chymotrypsin is supplied as a standard reagent for use in clinical quantitation of chymotrypsin activity in pancreatic juices and feces. Such assays are diagnostic for gastrointestinal and pancreatic disorders. Pancreatic elastase is also supplied commercially as a reagent for quantitation of xcex11-antitrypsin in plasma. Plasma xcex11-antitrypsin increases in concentration during the course of several inflammatory diseases, and xcex11-antitrypsin deficiencies are associated with increased incidence of lung disease. Compounds of the present invention can be used to enhance the accuracy and reproducibility of these assays by titrametric standardization of the commercial elastase supplied as a reagent. See, U.S. Pat. No. 4,499,082.
Protease activity in certain protein extracts during purification of particular proteins is a recurring problem which can complicate and compromise the results of protein isolation procedures. Certain proteases present in such extracts can be inhibited during purification steps by compounds of the present invention, which bind tightly to various proteolytic enzymes.
The pharmaceutical compositions of the invention can be administered to any animal that can experience the beneficial effects of the compounds of the invention. Foremost among such animals are humans, although the invention is not intended to be so limited.
The pharmaceutical compositions of the present invention can be administered by any means that achieve their intended purpose. For example, administration can be by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal, or ocular routes. Alternatively, or concurrently, administration can be by the oral route. The dosage administered will be dependent upon the age, health, and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired.
In addition to the pharmacologically active compounds, the new pharmaceutical preparations can contain suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries that facilitate processing of the active compounds into preparations that can be used pharmaceutically.
The pharmaceutical preparations of the present invention are manufactured in a manner that is, itself, known, for example, by means of conventional mixing, granulating, dragee-making, dissolving, or lyophilizing processes. Thus, pharmaceutical preparations for oral use can be obtained by combining the active compounds with solid excipients, optionally grinding the resulting mixture and processing the mixture of granules, after adding suitable auxiliaries, if desired or necessary, to obtain tablets or dragee cores.
Suitable excipients are, in particular, fillers such as saccharides, for example, lactose or sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example, tricalcium phosphate or calcium hydrogen phosphate, as well as binders, such as, starch paste, using, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone. If desired, disintegrating agents can be added, such as, the above-mentioned starches and also carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as, sodium alginate. Auxiliaries are, above all, flow-regulating agents and lubricants, for example, silica, talc, stearic acid or salts thereof, such as, magnesium stearate or calcium stearate, and/or polyethylene glycol. Dragee cores are provided with suitable coatings that, if desired, are resistant to gastric juices. For this purpose, concentrated saccharide solutions can be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol, and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. In order to produce coatings resistant to gastric juices, solutions of suitable cellulose preparations, such as, acetylcellulose phthalate or hydroxypropylmethyl-cellulose phthalate, are used. Dye stuffs or pigments can be added to the tablets or dragee coatings, for example, for identification or in order to characterize combinations of active compound doses.
Other pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as, glycerol or sorbitol. The push-fit capsules can contain the active compounds in the form of granules that may be mixed with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds are preferably dissolved or suspended in suitable liquids, such as, fatty oils or liquid paraffin. In addition, stabilizers may be added.
Suitable formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form, for example, water-soluble salts, alkaline solutions and cyclodextrin inclusion complexes. Especially preferred salts are hydrochloride and acetate salts. One or more modified or unmodified cyclodextrins can be employed to stabilize and increase the water solubility of compounds of the present invention. Useful cyclodextrins for this purpose are disclosed in U.S. Pat. Nos. 4,727,064, 4,764,604, and 5,024,998.
In addition, suspensions of the active compounds as appropriate oily injection suspensions can be administered. Suitable lipophilic solvents or vehicles include fatty oils, for example, sesame oil, or synthetic fatty acid esters, for example, ethyl oleate or triglycerides or polyethylene glycol-400 (the compounds are soluble in PEG-400). Aqueous injection suspensions can contain substances that increase the viscosity of the suspension, for example, sodium carboxymethyl cellulose, sorbitol, and/or dextran. Optionally, the suspension may also contain stabilizers.
The following examples are illustrative, but not limiting, of the method and compositions of the present invention. Other suitable modifications and adaptations of the variety of conditions and parameters normally encountered and obvious to those skilled in the art are within the spirit and scope of the invention.